WAS

Summary

WAS (WASP actin nucleation promoting factor, HGNC:12731) is a protein-coding gene on chromosome Xp11.23, encoding Actin nucleation-promoting factor WAS (P42768). Effector protein for Rho-type GTPases that regulates actin filament reorganization via its interaction with the Arp2/3 complex. It is haploinsufficient (ClinGen: sufficient evidence).

The Wiskott-Aldrich syndrome (WAS) family of proteins share similar domain structure, and are involved in transduction of signals from receptors on the cell surface to the actin cytoskeleton. The presence of a number of different motifs suggests that they are regulated by a number of different stimuli, and interact with multiple proteins. Recent studies have demonstrated that these proteins, directly or indirectly, associate with the small GTPase, Cdc42, known to regulate formation of actin filaments, and the cytoskeletal organizing complex, Arp2/3. Wiskott-Aldrich syndrome is a rare, inherited, X-linked, recessive disease characterized by immune dysregulation and microthrombocytopenia, and is caused by mutations in the WAS gene. The WAS gene product is a cytoplasmic protein, expressed exclusively in hematopoietic cells, which show signalling and cytoskeletal abnormalities in WAS patients. A transcript variant arising as a result of alternative promoter usage, and containing a different 5’ UTR sequence, has been described, however, its full-length nature is not known.

Source: NCBI Gene 7454 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked severe congenital neutropenia (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 778 total — 146 pathogenic, 52 likely-pathogenic
• Phenotypes (HPO): 97
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000377

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12731
Approved symbol	WAS
Name	WASP actin nucleation promoting factor
Location	Xp11.23
Locus type	gene with protein product
Status	Approved
Aliases	WASP, WASPA
Ensembl gene	ENSG00000015285
Ensembl biotype	protein_coding
OMIM	300392
Entrez	7454

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 15 protein_coding, 4 retained_intron

ENST00000376701, ENST00000450772, ENST00000470107, ENST00000474174, ENST00000483750, ENST00000490627, ENST00000698625, ENST00000698626, ENST00000698635, ENST00000906191, ENST00000906192, ENST00000906193, ENST00000906194, ENST00000906195, ENST00000906196, ENST00000906197, ENST00000906198, ENST00000906199, ENST00000906200

RefSeq mRNA: 1 — MANE Select: NM_000377 NM_000377

CCDS: CCDS14303

Canonical transcript exons

ENST00000376701 — 12 exons

Exon	Start	End
ENSE00000867104	48691107	48691427
ENSE00001707442	48683799	48683985
ENSE00003539440	48684283	48684423
ENSE00003543007	48686081	48686134
ENSE00003544043	48685946	48685987
ENSE00003547357	48685734	48685836
ENSE00003612781	48685547	48685633
ENSE00003974195	48688054	48688096
ENSE00003974199	48686781	48686955
ENSE00003974200	48688300	48688453
ENSE00003974202	48688660	48689066
ENSE00003974203	48689320	48689434

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 99.11.

FANTOM5 (CAGE): breadth broad, TPM avg 39.1652 / max 2234.4618, expressed in 657 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196276	37.2336	624
196281	0.6160	229
196278	0.4317	117
196275	0.4038	209
196274	0.2702	104
196277	0.0886	57
196279	0.0675	35
196280	0.0537	17

Top tissues by expression

282 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.11	gold quality
leukocyte	CL:0000738	98.44	gold quality
mononuclear cell	CL:0000842	98.41	gold quality
monocyte	CL:0000576	98.40	gold quality
blood	UBERON:0000178	98.20	gold quality
vermiform appendix	UBERON:0001154	96.87	gold quality
spleen	UBERON:0002106	96.82	gold quality
ileal mucosa	UBERON:0000331	95.70	gold quality
bone marrow cell	CL:0002092	95.24	gold quality
endometrium epithelium	UBERON:0004811	95.01	gold quality
lymph node	UBERON:0000029	94.66	gold quality
bone marrow	UBERON:0002371	93.63	gold quality
trabecular bone tissue	UBERON:0002483	93.51	gold quality
superficial temporal artery	UBERON:0001614	92.93	gold quality
periodontal ligament	UBERON:0008266	92.86	gold quality
caecum	UBERON:0001153	92.50	gold quality
Brodmann (1909) area 10	UBERON:0013541	92.30	silver quality
cranial nerve II	UBERON:0000941	91.94	gold quality
right lung	UBERON:0002167	91.08	gold quality
frontal pole	UBERON:0002795	90.58	gold quality
upper lobe of left lung	UBERON:0008952	90.27	gold quality
upper lobe of lung	UBERON:0008948	89.36	gold quality
gall bladder	UBERON:0002110	89.29	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.48	gold quality
cervix squamous epithelium	UBERON:0006922	87.95	silver quality
middle frontal gyrus	UBERON:0002702	87.41	silver quality
small intestine	UBERON:0002108	86.27	gold quality
upper leg skin	UBERON:0004262	86.25	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	85.32	gold quality
epithelium of nasopharynx	UBERON:0001951	84.99	silver quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-10	yes	27.31
E-MTAB-6701	yes	20.30
E-ANND-3	yes	16.23
E-CURD-88	yes	4.39

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ETS1, MYB, SP1, SPI1

miRNA regulators (miRDB)

34 targeting WAS, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-3147	99.52	66.34	388
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-7109-5P	99.18	66.13	1057
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4751	98.80	64.95	525
HSA-MIR-5089-5P	98.45	66.06	1388
HSA-MIR-1262	98.17	66.52	757
HSA-MIR-4701-3P	98.17	66.25	788
HSA-MIR-6736-5P	98.17	66.43	760
HSA-MIR-6515-5P	97.08	65.48	1219
HSA-MIR-3116	97.07	65.78	1324
HSA-MIR-3189-3P	96.80	66.34	896
HSA-MIR-3976	96.67	67.79	1187

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• WASp mediates actin polymerization and leads to ultimately to occupancy-induced TCR endocytosis (PMID:11748279)
• mutational analysis in patients with Wiskott-Aldrich syndrome in Argentina (PMID:11793485)
• Missense mutations of the WASP gene cause intermittent X-linked thrombocytopenia (PMID:11877312)
• Normal chemotactic responses were restored in WASp macrophages transfected with a full-length human WAS construct. Expression of exogenous WAS protein (WASp) in these cells also restored normal polarised cell morphology and the ability to form podosomes. (PMID:11950596)
• An Alu-mediated deletion at Xp11.23 leading to Wiskott-Aldrich syndrome. (PMID:12073025)
• Five novel WASP mutations have been identified that are all predicted to lead to premature translational termination of the WAS protein. (PMID:12124997)
• Activation of Wiskott-Aldrich syndrome protein and its association with other proteins by stromal cell-derived factor-1alpha is associated with cell migration in Jurkat cells, a T-lymphocyte line. (PMID:12135674)
• Required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses (PMID:12177428)
• Wiskott-Aldrich Syndrome protein regulates lipid raft dynamics during immunological synapse formation (PMID:12196287)
• Platelets activate Arp2/3 complex, assemble actin, and change shape in the absence of WASp, indicating a more specialized role for WASp in these cells. (PMID:12200375)
• Data show that the Src family kinase Hck induces phosphorylation of Wiskott Aldrich syndrome protein (WASp)-Tyr(291) independently of Cdc42 and that this causes a shift in the mobility of WASp upon SDS-PAGE. (PMID:12235133)
• mutated in Wiskott Aldrich syndrome (PMID:12351383)
• Results suggest that recruitment of factors by Wiskott-Aldrich Syndrome protein (WASP) and Scar1 stimulates cellular actin-based motility and actin nucleation with the Arp2/3 complex. (PMID:12429845)
• results suggest that the ZAP-70-CrkL-WIP pathway and PKCtheta link TCR to WASP activation (PMID:12504004)
• PSTPIP1 acts downstream of CD2/CD2AP to link CD2 engagement to the WASp-evoked actin polymerization required for synapse formation and T cell activation. (PMID:12530983)
• X-linked thrombocytopenia caused by a mutation in the WAS gene that disrupts interaction with the (WASP)-interacting protein (WIP). (PMID:12591280)
• Results describe somatic mosaicism in two brothers affected with Wiskott-Aldrich syndrome (WAS) due to a second-site mutation in the WAS protein (WASP) gene. (PMID:12727931)
• Phosphorylation plays a critical role in WASP function as a regulator of arp-2- and arp-3-mediated actin polymerization. (PMID:12791263)
• WAS protein expression is a useful tool for predicting long-term prognosis for patients with Wiskott-Aldrich syndrome. (PMID:12969986)
• Differentiation and survival of B lymphocytes is minimally dependent on WAS protein. (PMID:14504083)
• the interaction of the betaPIX.WASP.SPIN90 complex with Nck is crucial for stable cell adhesion and can be dynamically modulated by SPIN90 phosphorylation that is dependent on cell adhesion and ERK activation (PMID:14559906)
• WASp undergoes tyrosine phosphorylation upon CD16 or beta2-integrin engagement on NK cells. (PMID:15001467)
• WASp is either not involved in or is redundant in the rapid dynamics of lymphocyte microvilli. (PMID:15130947)
• interactions of WASP and WIP are affected by two novel mutations that change the conformation of WASP and disrupt hydrogen bonding (PMID:15469902)
• Mutations identified included p.R13X, p.R41X, p.S82P, IVS1-1 G –> C, p.L342TFsX493, and a large deletion. (PMID:15497008)
• The Wiskott-Aldrich WASP protein is an important component for integration of signals leading to nuclear translocation of transcription factors NFAT2 and NF-kappa B RelA during cell-cell contact and natural cytotoxicity receptor NKp46-dependent signaling. (PMID:15728466)
• Results describe a quantitative model of allosteric regulation of the Wiskott-Aldrich syndrome protein (WASP) by the Rho GTPase Cdc42. (PMID:15821030)
• The selective advantage of WASP+ natural killer cells was also demonstrated for carrier females (PMID:15985539)
• Knowledge of the molecular effect of WAS protein mutations provides a logical basis for correlating genotype and clinical phenotype of Wiskott-Aldrich syndrome (PMID:16002738)
• The process is a prerequisite for WASp activation and a critical step in temporal regulation and integration of WASp-mediated cellular responses. (PMID:16246732)
• TRAP and WASp, but not other unrelated aldolase binders, compete for the binding to the enzyme in vitro. (PMID:16278221)
• NMR investigation and cross-linking studies of the interaction of the Arp2/3 complex with VCA peptides of Wiskott-Aldrich syndrome protein (PMID:16285728)
• WASP and N-WASP are activated and phosphorylated by protein-tyrosine kinase and GTPase signals (PMID:16293614)
• A partial down-regulation of WASP is sufficient to inhibit podosome formation in dendritic cells. (PMID:16360341)
• A novel Wiskott-Aldrich syndrome protein (WASP) complex mutation identified in a WAS patient results in an aberrant product at the C-terminus from two transcripts with unusual polyA signals. (PMID:16372137)
• Human WASP suppresses the growth defect of Saccharomyces cerevisiae las17Delta strain, only in the presence of WASP-interacting protein (WIP). (PMID:16488394)
• The results strongly suggest that the smaller WASP is translated from the second ATG downstream of the original mutation, and not only T cells but also NK cells carrying the second mutation acquired a growth advantage over WASP negative counterparts. (PMID:16511828)
• WASP binds to the calcium- and integrin-binding protein (CIB) in platelets. (PMID:16582881)
• In addition to chemotaxis, the WASP-verprolin complex is involved in both podosome formation and phagocytosis. (PMID:16709815)
• activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia (PMID:16804117)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	wasa	ENSDARG00000015149
danio_rerio	wasb	ENSDARG00000026350
mus_musculus	Was	ENSMUSG00000031165
rattus_norvegicus	Was	ENSRNOG00000031058
caenorhabditis_elegans		WBGENE00007840
caenorhabditis_elegans		WBGENE00015100
caenorhabditis_elegans		WBGENE00015107

Paralogs (1): WASL (ENSG00000106299)

Protein

Protein identifiers

Actin nucleation-promoting factor WAS — P42768 (reviewed: P42768)

Alternative names: Wiskott-Aldrich syndrome protein

All UniProt accessions (4): P42768, A0A8V8TM35, A0A8V8TNH9, C9J3B7

UniProt curated annotations — full annotation on UniProt →

Function. Effector protein for Rho-type GTPases that regulates actin filament reorganization via its interaction with the Arp2/3 complex. Important for efficient actin polymerization. Possible regulator of lymphocyte and platelet function. Mediates actin filament reorganization and the formation of actin pedestals upon infection by pathogenic bacteria. In addition to its role in the cytoplasmic cytoskeleton, also promotes actin polymerization in the nucleus, thereby regulating gene transcription and repair of damaged DNA. Promotes homologous recombination (HR) repair in response to DNA damage by promoting nuclear actin polymerization, leading to drive motility of double-strand breaks (DSBs).

Subunit / interactions. Binds the Arp2/3 complex. Interacts with CDC42, RAC, NCK, HCK, FYN, SRC kinase FGR, BTK, ABL1, PSTPIP1, WIP, and to the p85 subunit of PLC-gamma. Interacts (via C-terminus) with ALDOA. Interacts with NCK1 (via SH3 domains). Interacts with FCHSD2. (Microbial infection) Interacts with E.coli effector protein EspF(U).

Subcellular location. Cytoplasm. Cytoskeleton. Nucleus.

Tissue specificity. Expressed predominantly in the thymus. Also found, to a much lesser extent, in the spleen.

Post-translational modifications. Phosphorylated at Tyr-291 by FYN and HCK, inducing WAS effector activity after TCR engagement. Phosphorylation at Tyr-291 enhances WAS activity in promoting actin polymerization and filopodia formation.

Disease relevance. Wiskott-Aldrich syndrome (WAS) [MIM:301000] An X-linked recessive immunodeficiency characterized by eczema, thrombocytopenia, recurrent infections, and bloody diarrhea. Death usually occurs before age 10. The disease is caused by variants affecting the gene represented in this entry. Thrombocytopenia 1 (THC1) [MIM:313900] A form of thrombocytopenia, a hematologic disorder defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting. The disease is caused by variants affecting the gene represented in this entry. Neutropenia, severe congenital, X-linked (XLN) [MIM:300299] A disorder of hematopoiesis characterized by maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The WH1 (Wasp homology 1) domain may bind a Pro-rich ligand. The CRIB (Cdc42/Rac-interactive-binding) region binds to the C-terminal WH2 domain in the autoinhibited state of the protein. Binding of Rho-type GTPases to the CRIB induces a conformation change and leads to activation.

RefSeq proteins (1): NP_000368* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000095	CRIB_dom	Domain
IPR000697	WH1/EVH1_dom	Domain
IPR003124	WH2_dom	Domain
IPR011026	WAS_C	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR033927	WASPfam_EVH1	Domain
IPR036936	CRIB_dom_sf	Homologous_superfamily

Pfam: PF00568, PF00786, PF02205

UniProt features (58 total): sequence variant 31, helix 5, modified residue 4, turn 4, compositionally biased region 3, domain 3, repeat 2, region of interest 2, initiator methionine 1, chain 1, sequence conflict 1, strand 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
2OT0	X-RAY DIFFRACTION	2.05
2A3Z	X-RAY DIFFRACTION	2.08
1CEE	SOLUTION NMR
1EJ5	SOLUTION NMR
1T84	SOLUTION NMR
2K42	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P42768-F1	70.84	0.26

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (4): 221, 291, 483, 484

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-202433	Generation of second messenger molecules
R-HSA-2029482	Regulation of actin dynamics for phagocytic cup formation
R-HSA-5663213	RHO GTPases Activate WASPs and WAVEs
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013409	RHOJ GTPase cycle
R-HSA-9664422	FCGR3A-mediated phagocytosis

MSigDB gene sets: 516 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, REACTOME_INNATE_IMMUNE_SYSTEM, GNF2_MSN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, MODULE_45, HALMOS_CEBPA_TARGETS_UP, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, RACCACAR_AML_Q6, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (21): regulation of T cell antigen processing and presentation (GO:0002625), defense response (GO:0006952), immune response (GO:0006955), blood coagulation (GO:0007596), regulation of actin polymerization or depolymerization (GO:0008064), actin polymerization or depolymerization (GO:0008154), epidermis development (GO:0008544), regulation of lamellipodium assembly (GO:0010591), endosomal transport (GO:0016197), actin filament polymerization (GO:0030041), actin filament-based movement (GO:0030048), Cdc42 protein signal transduction (GO:0032488), T cell activation (GO:0042110), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of stress fiber assembly (GO:0051492), negative regulation of stress fiber assembly (GO:0051497), protein-containing complex assembly (GO:0065003), cellular response to type II interferon (GO:0071346), positive regulation of double-strand break repair via homologous recombination (GO:1905168), negative regulation of cell motility (GO:2000146), actin filament organization (GO:0007015)

GO Molecular Function (8): actin binding (GO:0003779), SH3 domain binding (GO:0017124), protein kinase binding (GO:0019901), GTPase regulator activity (GO:0030695), small GTPase binding (GO:0031267), identical protein binding (GO:0042802), phospholipase binding (GO:0043274), protein binding (GO:0005515)

GO Cellular Component (13): nucleus (GO:0005634), cytosol (GO:0005829), actin filament (GO:0005884), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), vesicle membrane (GO:0012506), actin cytoskeleton (GO:0015629), site of double-strand break (GO:0035861), phagocytic vesicle (GO:0045335), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
RHO GTPase cycle	3
TCR signaling	1
Fcgamma receptor (FCGR) dependent phagocytosis	1
RHO GTPase Effectors	1
Leishmania phagocytosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
actin polymerization or depolymerization	2
stress fiber assembly	2
T cell antigen processing and presentation	1
regulation of antigen processing and presentation	1
regulation of T cell mediated immunity	1
response to stress	1
immune system process	1
response to stimulus	1
hemostasis	1
wound healing	1
coagulation	1
regulation of actin filament length	1
regulation of actin filament organization	1
actin filament organization	1
tissue development	1
lamellipodium assembly	1
regulation of plasma membrane bounded cell projection assembly	1
regulation of lamellipodium organization	1
vesicle-mediated transport	1
intracellular transport	1
protein polymerization	1
actin filament-based process	1
Rho protein signal transduction	1
lymphocyte activation	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
regulation of actin filament bundle assembly	1
regulation of actomyosin structure organization	1
negative regulation of actin filament bundle assembly	1
regulation of stress fiber assembly	1
cellular component assembly	1
protein-containing complex organization	1
response to type II interferon	1
cellular response to cytokine stimulus	1
double-strand break repair via homologous recombination	1
regulation of double-strand break repair via homologous recombination	1
positive regulation of DNA recombination	1
positive regulation of double-strand break repair	1

Protein interactions and networks

STRING

3020 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WAS	WIPF1	O43516	999
WAS	CDC42	P21181	999
WAS	NCK1	P16333	998
WAS	ACTR2	P61160	998
WAS	TRIP10	Q15642	996
WAS	HCLS1	P14317	995
WAS	CTTN	Q14247	994
WAS	PFN1	P07737	991
WAS	PFN4	Q8NHR9	984
WAS	PSTPIP1	O43586	984
WAS	PFN3	P60673	980
WAS	SRC	P12931	973
WAS	AKT1	P31749	973
WAS	GRB2	P29354	970
WAS	ARPC2	O15144	945

IntAct

145 interactions, top by confidence:

A	B	Type	Score
WAS	WIPF1	psi-mi:“MI:0915”(physical association)	0.970
WIPF1	WAS	psi-mi:“MI:0915”(physical association)	0.970
WIPF1	WAS	psi-mi:“MI:0403”(colocalization)	0.970
CDC42	WAS	psi-mi:“MI:0915”(physical association)	0.950
WAS	CDC42	psi-mi:“MI:0915”(physical association)	0.950
CDC42	WAS	psi-mi:“MI:0407”(direct interaction)	0.950

BioGRID (155): WIPF1 (Two-hybrid), NCK2 (Two-hybrid), SORBS2 (Two-hybrid), APPBP2 (Two-hybrid), ABI3 (Two-hybrid), WAS (Two-hybrid), WAS (Two-hybrid), TRIP10 (Two-hybrid), WAS (Affinity Capture-MS), WAS (Affinity Capture-Western), GAS7 (Affinity Capture-Western), SAE1 (Affinity Capture-MS), UBA2 (Affinity Capture-MS), UBE2I (Affinity Capture-MS), RANBP2 (Affinity Capture-MS)

ESM2 similar proteins: A4IG59, A7Z063, A8K0Z3, A8MWX3, B0BN56, B2RYF7, B5DEB9, C4AMC7, D4A702, F1RCE7, O08719, O48713, O75061, P42768, P50551, P50552, P70315, P70429, P70460, Q08BD8, Q0VBD2, Q27974, Q28DN4, Q2TA49, Q32N92, Q5R896, Q5RHY1, Q5U4A3, Q5XG48, Q5ZKA6, Q61733, Q68FU8, Q6VEQ5, Q7JW27, Q7L590, Q80TZ3, Q8BH43, Q8BYZ1, Q8CH02, Q8IWZ8

Diamond homologs: O00401, O08816, O36027, P42768, P70315, Q12446, Q91YD9, Q95107

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
CSNK2A1	up-regulates	WAS	phosphorylation
PTPN12	down-regulates	WAS	dephosphorylation
CSNK2A2	“up-regulates activity”	WAS	phosphorylation
WAS	“up-regulates activity”	ARP2/3	binding
CDC42	“up-regulates activity”	WAS	binding
BTK	“up-regulates activity”	WAS	phosphorylation
LYN	“up-regulates activity”	WAS	phosphorylation
FYN	“up-regulates activity”	WAS	phosphorylation
BTK	unknown	WAS	phosphorylation
PTPN12	“down-regulates activity”	WAS	dephosphorylation
HCK	“up-regulates activity”	WAS	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 54 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RHO GTPases Activate WASPs and WAVEs	9	73.2×	4e-13
FCGR3A-mediated phagocytosis	12	57.6×	2e-16
DAP12 signaling	6	56.7×	5e-08
FCERI mediated Ca+2 mobilization	5	45.8×	3e-06
Parasite infection	5	44.4×	3e-06
Leishmania phagocytosis	5	44.4×	3e-06
Regulation of actin dynamics for phagocytic cup formation	9	42.5×	5e-11
GPVI-mediated activation cascade	5	39.6×	4e-06

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of actin filament polymerization	8	54.0×	1e-09
B cell receptor signaling pathway	6	49.1×	3e-07
negative regulation of T cell receptor signaling pathway	5	37.4×	1e-05
T cell activation	6	31.8×	2e-06
T cell receptor signaling pathway	9	27.9×	9e-09
protein dephosphorylation	5	22.6×	1e-04
regulation of cell shape	9	22.6×	4e-08
regulation of actin cytoskeleton organization	7	22.5×	2e-06

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — MBL.

Clinical variants and AI predictions

ClinVar

778 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	146
Likely pathogenic	52
Uncertain significance	216
Likely benign	244
Benign	29

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073358	NM_000377.3(WAS):c.753dup (p.Trp252fs)	Pathogenic
1074326	NM_000377.3(WAS):c.827_828insGGGCCTTCTCCAGGGCAGGAAT (p.Ile276fs)	Pathogenic
1074601	NM_000377.3(WAS):c.1453+2T>G	Pathogenic
1074623	NM_000377.3(WAS):c.539dup (p.His180fs)	Pathogenic
11113	NM_000377.3(WAS):c.177del (p.Gly60fs)	Pathogenic
11114	NM_000377.3(WAS):c.257G>T (p.Arg86Leu)	Pathogenic
11115	NM_000377.3(WAS):c.257G>A (p.Arg86His)	Pathogenic
11116	NM_000377.3(WAS):c.167C>T (p.Ala56Val)	Pathogenic
11117	NM_000377.3(WAS):c.707C>G (p.Ala236Gly)	Pathogenic
11118	NM_000377.3(WAS):c.482dup (p.Pro162fs)	Pathogenic
11119	NM_000377.3(WAS):c.100C>T (p.Arg34Ter)	Pathogenic
11120	NM_000377.3(WAS):c.1A>T (p.Met1Leu)	Pathogenic
11121	NM_000377.3(WAS):c.389ACGAGG[3] (p.130DE[3])	Pathogenic
11123	NM_000377.3(WAS):c.134C>T (p.Thr45Met)	Pathogenic
11124	NM_000377.3(WAS):c.1097del (p.Gly366fs)	Pathogenic
11126	NM_000377.3(WAS):c.173C>G (p.Pro58Arg)	Pathogenic
11127	NM_000377.3(WAS):c.1442T>A (p.Ile481Asn)	Pathogenic
11128	WAS, 15,800-BP DEL	Pathogenic
11130	NM_000377.3(WAS):c.560-1G>A	Pathogenic
11131	NM_000377.3(WAS):c.559+2T>G	Pathogenic
11132	NM_000377.3(WAS):c.11del (p.Gly4fs)	Pathogenic
11133	NM_000377.3(WAS):c.73_74del (p.Thr25fs)	Pathogenic
1176930	NM_000377.3(WAS):c.295C>T (p.Gln99Ter)	Pathogenic
1200930	NM_000377.3(WAS):c.724del (p.Ser242fs)	Pathogenic
1321313	NM_000377.3(WAS):c.990del (p.Ile331fs)	Pathogenic
1338374	NM_000377.3(WAS):c.192G>A (p.Trp64Ter)	Pathogenic
1360224	NM_000377.3(WAS):c.176del (p.Pro59fs)	Pathogenic
1410526	NM_000377.3(WAS):c.382T>C (p.Phe128Leu)	Pathogenic
1418621	NM_000377.3(WAS):c.1021_1022insT (p.Pro341fs)	Pathogenic
1441543	NM_000377.3(WAS):c.1085del (p.Pro362fs)	Pathogenic

SpliceAI

1420 predictions. Top by Δscore:

Variant	Effect	Δscore
X:48683981:GCTTG:G	donor_gain	1.0000
X:48683982:CTTGG:C	donor_loss	1.0000
X:48683983:TTGG:T	donor_loss	1.0000
X:48683986:G:GG	donor_gain	1.0000
X:48683986:GTGAG:G	donor_loss	1.0000
X:48683987:T:A	donor_loss	1.0000
X:48686132:G:GT	donor_gain	1.0000
X:48686778:CA:C	acceptor_loss	1.0000
X:48686779:A:AG	acceptor_gain	1.0000
X:48686779:AG:A	acceptor_gain	1.0000
X:48686780:G:GG	acceptor_gain	1.0000
X:48686780:GG:G	acceptor_gain	1.0000
X:48686908:G:GT	donor_gain	1.0000
X:48686908:G:T	donor_gain	1.0000
X:48686956:G:GG	donor_gain	1.0000
X:48686959:A:T	donor_gain	1.0000
X:48687023:C:G	donor_gain	1.0000
X:48687034:G:GT	donor_gain	1.0000
X:48688294:G:A	acceptor_gain	1.0000
X:48688438:GAGA:G	donor_gain	1.0000
X:48688452:GG:G	donor_gain	1.0000
X:48688452:GGGT:G	donor_loss	1.0000
X:48688453:GG:G	donor_gain	1.0000
X:48688454:G:GC	donor_loss	1.0000
X:48688454:G:GG	donor_gain	1.0000
X:48688455:T:G	donor_loss	1.0000
X:48683982:CTTG:C	donor_gain	0.9900
X:48683983:TTG:T	donor_gain	0.9900
X:48683984:TG:T	donor_gain	0.9900
X:48683985:GG:G	donor_gain	0.9900

AlphaMissense

3200 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:48686951:T:C	F244L	1.000
X:48686952:T:C	F244S	1.000
X:48686952:T:G	F244C	1.000
X:48686953:C:A	F244L	1.000
X:48686953:C:G	F244L	1.000
X:48686934:T:A	I238N	0.999
X:48686951:T:G	F244V	0.999
X:48688055:C:A	H246N	0.999
X:48688055:C:G	H246D	0.999
X:48688056:A:G	H246R	0.999
X:48688057:T:A	H246Q	0.999
X:48688057:T:G	H246Q	0.999
X:48688064:C:G	H249D	0.999
X:48688066:C:A	H249Q	0.999
X:48688066:C:G	H249Q	0.999
X:48688071:G:A	G251E	0.999
X:48688073:T:A	W252R	0.999
X:48688073:T:C	W252R	0.999
X:48688322:T:C	L267P	0.999
X:48688334:T:C	F271S	0.999
X:48688349:T:C	I276T	0.999
X:48688349:T:G	I276S	0.999
X:48688364:T:C	L281P	0.999
X:48688391:T:A	I290N	0.999
X:48688403:T:A	I294N	0.999
X:48689041:T:C	I438T	0.999
X:48689390:T:C	L470P	0.999
X:48686926:A:C	K235N	0.998
X:48686926:A:T	K235N	0.998
X:48686934:T:G	I238S	0.998

dbSNP variants (sampled 300 via entrez): RS1000499557 (X:48680337 A>G), RS1000658356 (X:48680906 T>A,C), RS1001438439 (X:48690548 T>C), RS1001501107 (X:48682427 A>C), RS1001656489 (X:48682858 G>A), RS1002634262 (X:48675637 T>C), RS1002917916 (X:48685130 C>T), RS1003208636 (X:48676049 C>A,T), RS1003508559 (X:48687665 G>T), RS1003639292 (X:48677358 C>T), RS1004759258 (X:48680231 C>T), RS1004915324 (X:48690049 A>G), RS1005643048 (X:48681958 C>A), RS1006198328 (X:48674994 G>C), RS1007699023 (X:48686657 A>T)

Disease associations

OMIM: gene MIM:300392 | disease phenotypes: MIM:300299, MIM:301000, MIM:313900

GenCC curated gene-disease

Disease	Classification	Inheritance
Wiskott-Aldrich syndrome	Definitive	X-linked
X-linked severe congenital neutropenia	Strong	X-linked
thrombocytopenia 1	Strong	X-linked

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked severe congenital neutropenia	Definitive	XL
Wiskott-Aldrich syndrome	Definitive	XL

Mondo (4): X-linked severe congenital neutropenia (MONDO:0010294), Wiskott-Aldrich syndrome (MONDO:0010518), thrombocytopenia 1 (MONDO:0010743), thrombocytopenia (MONDO:0002049)

Orphanet (4): Hereditary thrombocytopenia with normal platelets (Orphanet:268322), X-linked thrombocytopenia with normal platelets (Orphanet:852), X-linked severe congenital neutropenia (Orphanet:86788), Wiskott-Aldrich syndrome (Orphanet:906)

HPO phenotypes

97 total (30 of 97 shown, HPO-id order):

HPO	Term
HP:0000112	Nephropathy
HP:0000140	Abnormality of the menstrual cycle
HP:0000225	Gingival bleeding
HP:0000246	Sinusitis
HP:0000388	Otitis media
HP:0000389	Chronic otitis media
HP:0000403	Recurrent otitis media
HP:0000421	Epistaxis
HP:0000491	Keratitis
HP:0000498	Blepharitis
HP:0000509	Conjunctivitis
HP:0000778	Hypoplasia of the thymus
HP:0000964	Eczematoid dermatitis
HP:0000967	Petechiae
HP:0000978	Bruising susceptibility
HP:0000979	Purpura
HP:0001025	Urticaria
HP:0001287	Meningitis
HP:0001328	Specific learning disability
HP:0001369	Arthritis
HP:0001419	X-linked recessive inheritance
HP:0001645	Sudden cardiac death
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001878	Hemolytic anemia
HP:0001879	Abnormal eosinophil morphology
HP:0001880	Increased total eosinophil count
HP:0001888	Decreased total lymphocyte count
HP:0001890	Autoimmune hemolytic anemia
HP:0001891	Iron deficiency anemia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002401_286	Platelet distribution width	7.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007984	platelet component distribution width

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937
D014923	Wiskott-Aldrich Syndrome	C15.378.100.100.970; C15.378.243.750.605.900; C15.378.463.960; C15.378.553.546.605.900; C16.320.099.970; C16.320.322.937; C16.320.798.875; C20.673.627.900; C20.673.795.875
C564539	Neutropenia, Severe Congenital, X-Linked (supp.)
C564052	Thrombocytopenia 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases abundance, increases expression, affects expression	2
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	2
Estradiol	affects cotreatment, increases expression	2
Nickel	increases expression	2
Smoke	decreases expression, increases expression	2
Tretinoin	increases expression	2
aristolochic acid I	increases expression	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
quercitrin	affects expression	1
terbufos	decreases methylation	1
cobaltous chloride	increases expression	1
perfluorooctanoic acid	affects cotreatment, increases expression	1
butylidenephthalide	decreases expression	1
perfluorooctane sulfonic acid	affects cotreatment, increases expression	1
perfluorobutanesulfonic acid	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Atrazine	increases expression	1
Fonofos	decreases methylation	1
Ozone	affects expression, increases abundance	1
Parathion	decreases methylation	1
Plant Extracts	decreases expression, affects cotreatment	1
Progesterone	affects cotreatment, increases expression	1
Tamoxifen	decreases expression	1
Zinc	increases expression	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	decreases expression	1

Cellosaurus cell lines

13 cell lines: 6 cancer cell line, 4 transformed cell line, 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_2Z03	ID00003	Transformed cell line	Male
CVCL_2Z04	ID00004	Transformed cell line	Male
CVCL_A262	KCL029	Embryonic stem cell	Male
CVCL_D1RD	Abcam K-562 WAS KO	Cancer cell line	Female
CVCL_D2N0	Abcam Raji WAS KO	Cancer cell line	Male
CVCL_E1MI	HyCyte Ramos KO-hWAS	Cancer cell line	Male
CVCL_HL32	GM21867	Transformed cell line	Male
CVCL_HL33	GM21868	Transformed cell line	Male
CVCL_TX77	HAP1 WAS (-) 1	Cancer cell line	Male
CVCL_V158	AND-1 WASKO C1.1	Embryonic stem cell	Male

Clinical trials (associated diseases)

293 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01289847	PHASE4	COMPLETED	A Study to Find Out How Safe and Effective Gammaplex® is in Young People With Primary Immunodeficiency
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT00278954	PHASE3	COMPLETED	Efficacy, Safety and Pharmacokinetics of Gammaplex in Primary Immunodeficiency Diseases.
NCT03837483	PHASE3	ACTIVE_NOT_RECRUITING	A Clinical Study to Evaluate the Use of a Cryopreserved Formulation of OTL-103 in Subjects With Wiskott-Aldrich Syndrome
NCT04340700	PHASE3	WITHDRAWN	Characterization of the Pharmacodynamic Response to Vaped THC
NCT00037791	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00039910	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00073580	PHASE3	COMPLETED	Angiomax in Patients With HIT/HITTS Type II Undergoing Off-Pump Coronary Artery Bypass Grafting (CABG) (CHOOSE)
NCT00102323	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Refractory to Splenectomy
NCT00102336	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Prior to Splenectomy
NCT00116688	PHASE3	COMPLETED	Open Label Extension Study of Romiplostim (AMG 531) in Thrombocytopenic Patients With Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
NCT00128713	PHASE3	COMPLETED	Optimal Platelet Dose Strategy for Management of Thrombocytopenia
NCT00151866	PHASE3	COMPLETED	Efficacy of Transfusions With Platelets Stored in Platelet Additive Solution II Versus Plasma
NCT00261924	PHASE3	COMPLETED	Efficacy and Safety Study of Platelets Treated for Pathogen Inactivation and Stored for Up to Seven Days
NCT00415532	PHASE3	COMPLETED	Romiplostim (AMG 531) Versus Medical Standard of Care for Immune (Idiopathic) Thrombocytopenic Purpura
NCT00420914	PHASE3	TERMINATED	Strategies for Transfusion of Platelets (SToP)
NCT00501345	PHASE3	TERMINATED	Aspirin in Patients With Myocardial Infarction and Thrombocytopenia
NCT00508820	PHASE3	COMPLETED	An Open Label Study of Romiplostim in Adult Thrombocytopenic Subjects With ITP
NCT00678587	PHASE3	TERMINATED	Eltrombopag To Reduce The Need For Platelet Transfusion In Subjects With Chronic Liver Disease And Thrombocytopenia Undergoing Elective Invasive Procedures
NCT01438840	PHASE3	COMPLETED	Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults With Chronic Immune Thrombocytopenia (Amendment 02)
NCT01444417	PHASE3	COMPLETED	Safety and Efficacy Study of Romiplostim to Treat Immune Thrombocytopenia (ITP) in Pediatric Patients
NCT01805648	PHASE3	UNKNOWN	Efficacy and Safety Study of Maintenance Treatment With rhTPO in Thrombocytopenic Subjects With ITP
NCT02244658	PHASE3	UNKNOWN	Recombinant Human Thrombopoietin (rhTPO) in Management of Chemotherapy-induced Thrombocytopenia in Acute Myelocytic Leukemia
NCT02389621	PHASE3	COMPLETED	Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures
NCT02444728	PHASE3	TERMINATED	Cyclophosphamide and Hydroxychloroquine for Thrombocytopenia in SLE
NCT02487563	PHASE3	COMPLETED	Prospective Study of Patients With Thrombocytopenia Following HSCT